The class I family of receptor tyrosine kinases is described in Reese, M. D., et al, Stem Cells, 15, pages 1-8 (1997), the whole of which is incorporated herein by reference. Members of this family include HER-2/neu, HER-3, HER-4 and epidermal growth factor receptor (EGFR) and are single-chain membrane spanning proteins which have significant homology to one another including about 80% amino acid identity in the tyrosine kinase domain.
HER-2/neu (erbB-2) gene product is a 185-kDA transmembrane receptor tyrosine kinase that is described in some detail in said Reese et al publication and overexpression thereof has been associated with tumor growth in several kinds of cancer.
Recently enormous attention has been given to the importance of HER-2/neu in breast cancer. HER-2/neu is overexpressed in 20-30% of breast cancers and the increased expression has been associated with poor patient prognosis. This discovery has led to the development of HERCEPTIN.RTM., an antibody to HER-2/neu, which in tests has been found to lengthen remission time in metastatic breast cancer. HER-2/neu is a cell-surface receptor that transmits growth signals to the cell nucleus. HERCEPTIN.RTM. appears to block these signals thereby apparently inhibiting proliferation of cells mediated by HER-2/neu in HER-2/neu positive breast cancer.
Epidermal growth factor receptor (EGFR) is a 170 kDA glycoprotein. It is a prototypical transmembrane protein that consists of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain that possesses intrinsic tyrosine kinase activity. After ligand binding, EGFR undergoes dimerization which is essential for activation of its enzymatic kinase activity. EGFR is thus autophosphorylated and transphosphorylated on tyrosine residues, and the phosphorylated residues become the sites of association of effector proteins. Overexpressed EGFR is intimately involved in modulating the epidermal growth factor growth signal and is considered as likely to confer a growth advantage. This conclusion is supported by the observation that tumor growth in nude mice is inhibited by treatment with anti-EGFR antibodies and tumorigenicity in nude mice is inhibited through blockage of the tyrosine kinase activity of the receptor. EGFR has been found to be overexpressed in many malignancies. Anti-EGFR antibodies are being tested as therapy for malignancies overexpressing EGFR.
Peroxisome proliferator-activated receptor .gamma. (PPAR.gamma.) ligands are currently being used for treatment of type 2 diabetes. Moreover, MCF-7 and T47D human breast cancer cells have been found to contain a functional PPAR response; see Kilgour, M. W., et al, Mol. Cell Endocrinol, 129:2, 229-235 (May 5, 1997). Furthermore, a ligand for PPAR-.gamma. has been found to inhibit rat mammary carcinogenesis in NMU injected female Sprague Dawley rats; see Suh, N., et al, Cancer Research 59, 5671-5673 (Nov. 15, 1999). However, administration of PPAR.gamma. ligands has not heretofore been associated with decreasing levels of HER-2/neu or EGFR or of having therapeutic benefit based thereon in treating cancers associated with overexpression of these including the subset of breast cancer associated with overexpression of HER-2/neu.